Protection from lethal Gram-negative bacterial sepsis by targeting Toll-like receptor 4

Toll-like receptor 4 (TLR4), the signal-transducing molecule of the LPS receptor complex, plays a fundamental role in the sensing of LPS from Gram-negative bacteria. Activation of TLR4 signaling pathways by LPS is a critical upstream event in the pathogenesis of Gram-negative sepsis, making TLR4 an...

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Veröffentlicht in:Proceedings of the National Academy of Sciences - PNAS 2009-02, Vol.106 (7), p.2348-2352
Hauptverfasser: Roger, Thierry, Froidevaux, Céline, Le Roy, Didier, Reymond, Marlies Knaup, Chanson, Anne-Laure, Mauri, Davide, Burns, Kim, Riederer, Beat Michel, Akira, Shizuo, Calandra, Thierry
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Sprache:eng
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Zusammenfassung:Toll-like receptor 4 (TLR4), the signal-transducing molecule of the LPS receptor complex, plays a fundamental role in the sensing of LPS from Gram-negative bacteria. Activation of TLR4 signaling pathways by LPS is a critical upstream event in the pathogenesis of Gram-negative sepsis, making TLR4 an attractive target for novel antisepsis therapy. To validate the concept of TLR4-targeted treatment strategies in Gram-negative sepsis, we first showed that TLR4⁻/⁻ and myeloid differentiation primary response gene 88 (MyD88)⁻/⁻ mice were fully resistant to Escherichia coli-induced septic shock, whereas TLR2⁻/⁻ and wild-type mice rapidly died of fulminant sepsis. Neutralizing anti-TLR4 antibodies were then generated using a soluble chimeric fusion protein composed of the N-terminal domain of mouse TLR4 (amino acids 1-334) and the Fc portion of human IgG1. Anti-TLR4 antibodies inhibited intracellular signaling, markedly reduced cytokine production, and protected mice from lethal endotoxic shock and E. coli sepsis when administered in a prophylactic and therapeutic manner up to 13 h after the onset of bacterial sepsis. These experimental data provide strong support for the concept of TLR4-targeted therapy for Gram-negative sepsis.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0808146106